P951: IMPACT OF MEASURABLE RESIDUAL DISEASE (MRD) DIFFERENCES ON PROGRESSION-FREE SURVIVAL (PFS): AN AGGREGATE DATA ANALYSIS FROM RANDOMIZED CLINICAL TRIALS IN MULTIPLE MYELOMA (MM)
Authors: Bruno Paiva, Anastasiia Zherniakova, Jorge Nuñez, Paula Rodríguez-Otero, Qian Shi, Nikhil Munshi, Brian Durie, Jesús San Miguel
Journal: HemaSphere (2023)

Topic: 14. Myeloma and other monoclonal gammopathies - Clinical Background: The prognostic value of MRD in MM is well established. However, its role as a surrogate of treatment efficacy for potential use as an endpoint in MM clinical trials, remains undefined. Aims: Analyze the correlation between MRD negative rates and PFS benefit in randomized clinical trials across the spectrum of MM treatment with the purpose of evaluating the role of MRD as a surrogate endpoint. Methods: We searched for randomized clinical trials describing PFS and MRD data in >50 patients, using flow cytometry and/or next-generation sequencing methods with a reported minimum sensitivity of 10-5, in Medline articles and ASCO/ASH/EHA/IMS abstracts published until the 2nd of December 2022. Two independent investigators selected the articles and abstracts for potential inclusion; disagreements were resolved by a third investigator. The strength of the association between the treatment effect on PFS and the treatment effect on MRD negative rates was quantified with the trial-level coefficient of determination (R2trial) and the 95% confidence interval (95% CI). The analyses were weighted by the trial sample size. Results: Twenty clinical trials were identified; 9 in NDTE, 5 in NDTI and 6 in RRMM. The primary endpoint was meet in 16 of the 20 trials, and 10 new drugs or regimens were approved for the treatment of MM based on the positive results of these studies. The weighted R2trial (95% CI) observed in the aggregated analysis of the 20 clinical trials was 0.57 (95% CI 0.28 - 0.86, P <.001) (Fig. 1A). Sensitivity analyses using a leave-one-out approach showed consistent R2trial levels ranging from 0.46 to 0.62. Thus, MRD negative rates in MM randomized clinical trials are correlated with a treatment effect in PFS. Sub analysis according to disease setting showed a lower weighted R2trial in NDTE (0.30, 95% CI <0.01 – 0.83; P =.08) when compared to RRMM (0.67, 95% CI 0.06 – 1.00; P =.05) and NDTI (0.83, 95% CI 0.4 – 1.0; P =.03). Beyond the moderate weighted R2trial observed in this study, it would be valuable having an estimation of the magnitude of differences in MRD negativity that is needed for the prediction of a clinically meaningful improvement of PFS. Thus, we compared the difference in MRD negative rates between experimental vs control arms in clinical trials demonstrating a hazard ratio lower than 0.70. The median (p25 - p75) difference in MRD negative rates was significantly higher in clinical trials with a hazard ratio < 0.70 vs ≥ 0.70: 15% (6.65% - 21%) vs 2% (0.5% - 6.1%), respectively (P =.0001). There was nearly no overlap between p25 vs p75 difference in MRD negative rates observed in the former vs the later studies (Fig. 1B). These results suggest that treatment arms with scarce differences in MRD negative rates (e.g., <6%) will likely show no meaningful differences in PFS. We further stratified clinical trials according to tertiles of MRD negative rate differences observed between experimental vs control arms. The corresponding median (p25 - p75) difference in median PFS was 3.2 (0.2 – 20), 5.5 (5.2 – 9.6) and 17.1 (14 – 27.5) months in clinical trials where MRD negative rates differed in less than 3.2%, between 3.2% and 13.5%, and greater than 13.5% (Fig. 1C). These findings suggest that differences in MRD negative rates greater than 13.5%, which were observed in trials conducted in NDTE, NDTI and RRMM, could be a reasonable endpoint for the prediction of significantly improved PFS in randomized clinical trials. Summary/Conclusion: The outputs of this study suggest promising potential value and could provide guidance on the definition of MRD endpoints in MM.Keywords: MRD, Myeloma